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Presurgical evaluation in patients with hypothalamic hamartomas
Presurgical Assessment of the Epilepsies with Clinical Neurophysiology and Functional Imaging Handbook of Clinical Neurophysiology, Vol. 3 Felix Rosenow and Hans O. Lüders (Eds.) © 2004 Elsevier B.V. All rights reserved
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CHAPTER 3.7
Presurgical evaluation in patients with hypothalamic hamartomas A.S. Harveya,b,c,d,∗ , J.L. Freemanb,c,e and S.F. Berkovica,b,d,f a
Children’s Epilepsy Program, Royal Children’s Hospital, Melbourne, Australia b Comprehensive Epilepsy Programme, Austin Health, Melbourne, Australia c Department of Paediatrics, University of Melbourne, Melbourne, Australia d Epilepsy Research Collaborative Centre, University of Melbourne, Melbourne, Australia e Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia f Department of Medicine, University of Melbourne, Melbourne, Australia
1. Introduction Hypothalamic hamartomas (HH) are a rare brain malformation comprising a tumor-like mass of neuronal and glial tissue in the suprasellar region, typically attached to the mamillary bodies on one or both sides and extending antero-inferiorly from the tuber cinereum, with or without extension into the third ventricle above (Boyko et al., 1991). HH characteristically present with seizures, precocious puberty, or both (Diebler and Ponsot, 1983), although the relative incidence of their neurological and endocrinological manifestations is unknown (List et al., 1958). Seizures typically have their onset in infancy or early childhood and, with rare exceptions, are gelastic (laughing) and/or dacrystic (crying) in nature (Tassinari et al., 1997). The epilepsy associated with HH is usually resistant to treatment with antiepileptic medication and in many patients evolves to a symptomatic generalized epilepsy (SGE) with tonic–clonic seizures and drop attacks, often accompanied by neurobehavioral deterioration with intellectual disability and bouts of rage and aggression (Berkovic et al., 1988; Tassinari et al., 1997). A small number of patients have a milder form of epilepsy associated with normal intelligence, an aura described as “pressure to laugh”, infrequent gelastic seizures and rare complex partial or focal motor seizures (Sturm et al., 2000). ∗
Correspondence to: Dr. A. Simon Harvey, Epileptologist. Director, Children’s Epilepsy Program, Royal Children’s Hospital, Parkville, Melbourne, Australia 3052. E-mail address: [email protected] Tel.: +61-3-9345-5661; fax: +61-3-9345-5977.
HH associated with seizures usually have an intraventricular component and sessile attachment to the hypothalamus, whereas those associated with precocious puberty alone are either pedunculated in their attachment or do not distort the hypothalamus and third ventricular outline (Valdueza et al., 1994; Arita et al., 1999; Freeman et al., 2004). The basis of the seizure disorder seems to be an intrinsic epileptogenicity (Berkovic et al., 1997; Kuzniecky et al., 1997), and much of the electroclinical expression may be mediated by connections of the hamartoma or adjacent hypothalamus (Kahane et al., 1997; Freeman et al., 2003a). However, the considerable variability in seizure, cognitive and behavioral manifestations in patients with HH is largely unexplained and seems not to be due to differences in HH size and attachment. 2. Epilepsy surgery for hypothalamic hamartoma Given the often severe, refractory, and sometimes progressive nature of the epilepsy associated with HH, various surgical approaches have been employed to treat the seizures. Prior to the acceptance of HH origin of seizures in this syndrome, some patients underwent anterior temporal or frontal lobe resections due to pseudolocalization of seizures to these cortical regions, the results of which were universally disappointing (Cascino et al., 1993). Over the years, case reports of patients with refractory epilepsy treated with resection or disconnection of their HH have been published, the results being variable but encouraging. More recently, several groups have reported experience with larger numbers of patients treated with resection of the HH, employing various approaches. Classical
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subfrontal or transsylvian approaches to the HH from below have been most commonly employed, with a significant proportion of patients having residual lesion and postoperative seizures, and many suffering complications such as stroke, cranial neuropathy, or endocrine disturbance (Palmini et al., 2002). Delalande recently reported open and endoscopic approaches to disconnection of HH, with good seizure outcome and fewer operative complications than with pterional resection (Delalande and Fohlen, 2003). Our group has employed a transcallosal approach to resection of HH, this approach providing better access to the lesion and greater ability to resect what we believe to be the crucial component of the HH, that being the intraventricular component attached to the mammillary bodies (Rosenfeld et al., 2001). Results from surgery in over 29 children at our center indicate that approximately 50% are seizure-free, and most of the remainder have had worthwhile seizure reduction; furthermore, improvements in language, schooling, and behavior are almost universal in our operated patients, and neither permanent neurological nor significant endocrine disturbance have occurred (Freeman et al., 2003b; Harvey et al., 2003). This approach has also been employed in 6 adult patients (aged 20–33 years), with seizure improvement seen in all but 1 during limited follow-up (unpublished observations). Stereotactic radiosurgery with the gamma knife is reported to be successful in a similar proportion of patients (Regis et al., 2000; Dunoyer et al., 2002), with the suggestion that subnecrotic doses of radiation to the HH only are required. Radiofrequency thermocoagulation (Kuzniecky et al., 1997; Fukuda et al., 1999; Parrent, 1999) and endoscopic removal (Kuzniecky et al., 2002) are also reported. Presently, debate exists about the most effective and safest neurosurgical approach to these lesions, the selection of patients, the timing of surgery, and the long-term outcome following surgery.
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sis on proof of seizure localization to the lesion. The key elements of the presurgical investigation of patients with HH can be summarized as follows:
• Assessment of the patient’s epilepsy with regard to
•
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3. Preoperative investigation of hypothalamic hamartoma
• The investigation of patients with HH for potential epilepsy surgery, regardless of the operative approach employed, is similar to the investigation of patients with refractory epilepsy due to cerebral lesions. However, there are some important differences, including (1) the need for perioperative endocrine assessment; (2) the need for precise anatomical imaging of the midline structures of the brain; and (3) perhaps less empha-
seizure evolution over time, the likelihood of seizure origin in the HH, and the impact of seizures on the patient’s life. This is done with a detailed seizure history, routine scalp EEG, video–EEG monitoring, ictal single-photon emission computed tomography (SPECT), and intracranial EEG recording. The application of these modalities to the investigation of patients with HH is discussed in detail below. Characterization of the patient’s cognitive, behavioral, and psychiatric status, in particular the degree of any memory disturbance, intellectual disability, and episodic rage. This is generally done with a detailed developmental history, neuropsychological testing, and psychiatric evaluation. These aspects of the presurgical evaluation are not discussed here. Demonstration of the HH size, signal characteristics, attachment, lateralization, and relationship to normal structures (e.g. mamillary bodies, fornices, mamillothalamic tracts, hypothalamic nuclei), as well as exclusion of other potentially epileptogenic lesions such as cortical dysplasia. This is achieved with high-resolution magnetic resonance imaging (MRI) employing standard epilepsy protocols supplemented by thin T2-weighted slices in the three orthogonal planes through the HH and adjacent midline structures. The T2-weighted sequences are particularly important to provide maximum signal contrast between the hypothalamic nuclei (normal gray signal), the HH (usually high signal), and the heavily myelinated fornices, mammillary bodies, and mammillothalamic tracts (low signal). This aspect of the presurgical evaluation is particularly important in the assessment of surgical candidacy, the choice and planning of the surgical approach, and the postoperative assessment. MRI evaluation of HH is not discussed further here. Characterization of baseline endocrine status and reassessment following surgery is a crucial aspect of the perioperative management of all patients with HH, not only those with precocious puberty. Clinical and biochemical assessments of growth, thyroid, adrenal, and sexual function, as well as water balance and appetite, are obtained by clinical examination, hormone assays, and stimulation tests, not discussed further here.
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Fig. 1. Schematic representation of the age-related transition from gelastic to partial to tonic seizures that occurs in many patients with hypothalamic hamartoma and intractable epilepsy coming to presurgical evaluation. Gelastic features may persist as isolated gelastic seizures, be incorporated in partial and tonic seizures, or be replaced during this evolution.
The review that follows is concentrated on aspects of seizure analysis in HH with clinical, EEG, and SPECT modalities. Presurgical evaluation of endocrine status and MR imaging of HH are reviewed elsewhere (Freeman et al., 2003b; Freeman et al., 2004). 3.1. Seizure history and video analysis The epileptic syndrome in patients with HH is quite stereotyped, with gelastic (laughing) or dacrystic (crying) seizures almost universal. Variability in the age at seizure onset, frequency and severity of seizures, and degree of evolution to complex partial seizures (CPS) and to SGE accounts for most differences between patients (Fig. 1). Most patients presenting for surgery are children with multiple daily gelastic, complex partial and tonic seizures, many having a Lennox–Gastaut syndrome. In the RCH series of 29 patients, 2 had gelastic seizures only, 27 had CPS, and 22 had secondary generalized or tonic seizures (Harvey et al., 2003). Gelastic seizures are reported as beginning in the first year of life in over a third of patients (Tassinari et al., 1997); neonatal onset is common, and onset from the first day of life is well known (Sher and Brown, 1976; Diebler and Ponsot, 1983; Berkovic et al., 1988; Kuzniecky et al., 1997; DiFazio and Davis, 2000; Palmini et al., 2002; Freeman et al., 2003a). The seizures are stereotypical with bouts of laughter-like vocalization, associated with unilateral or bilateral facial contraction in the guise of a smile (Pendl, 1975) and with autonomic disturbance such as flushing, tachycardia, and modified respiration (Cerullo et al., 1998). In some patients, the sound produced has a crying quality, and the facial contraction mimics a grimace. There may also be a combination of gelastic and dacrystic seizures in the same patient (Breningstall, 1985) and in the same seizure (Kahane et al., 1997).
Older patients do not report a feeling of humour, and in fact, many report the feeling as unpleasant, or associated with epigastric or other discomfort (Striano et al., 1999). When assessable, the conscious state may not be impaired. In its mildest form, patients may simply report an urge to laugh that can be suppressed (Sturm et al., 2000). Gelastic seizures can occur with a very high frequency and periodicity, particularly in infants, and they often occur from sleep. Gelastic seizures are rarely diagnosed at onset. They may be mistaken for normal laughter, as in the case of one child who won a happy baby contest (Berkovic et al., 1988), or misdiagnosed as infantile colic. The presentation of gelastic seizures in early infancy illustrates the importance of parental interpretation of the vocalization and facial contraction in determining whether they are ultimately labeled as either gelastic or dacrystic; laughter in the neonatal period is developmentally precocious, raising the question of whether this is an appropriate description of the seizures (Berkovic et al., 1988). While the neuroanatomical basis of ictal laugher in patients with HH is not entirely known, there are reasons to suspect that electrical stimulation of the adjacent hypothalamus by the hamartoma is responsible. Mechanical stimulation of the floor of the third ventricle, for example, has been shown to induce laughter (Foerster and Gagel, 1933), as has acute subarachnoid hemorrhage adjacent to the mammillary bodies (Martin, 1950). Discussed in more detail below, stereotactic depth electrode encephalography has demonstrated origin of gelastic seizures within HH, but the seizure discharge remained confined to the HH in most cases, without involvement of the adjacent anterior and posterior hypothalamus where this could be determined (Munari et al., 1995). It should be remembered that laughter may be seen in patients with complex partial seizures of temporal and frontal origin (Arroyo et al., 1993; Biraben et al., 1999), in
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association with infantile spasms (Druckman and Chao, 1955; Druckman and Chao, 1957), and in metabolic and other degenerative diseases (Chen and Forster, 1973). The laughter associated with HH is often said to have a mechanical or unnatural quality, and it was previously proposed that the nature of the laughter might enable distinction between gelastic seizures of diencephalic and temporal origin (Gascon and Lombroso, 1971). In our experience, however, this is not so; laughter without an affective component may occur in temporal lobe seizures (Loiseau et al., 1971), and we have observed laughter in several of our HH patients that is both mirthful and has an infectious quality. Patients with HH may continue to have only gelastic seizures, but in many, there is progression during midchildhood to complex partial seizures. It is often this progression that alerts parents and physicians to the epileptic nature of the laughter attacks. CPS in patients with HH typically manifest as behavioral arrest and staring, often with preceding or accompanying laughter and autonomic disturbance. Epigastric discomfort and fear may be present, as in typical mesial temporal lobe epilepsy, but experiential and psychic phenomena are rare. Simple gestural and oroalimentary automatisms, axial movements, and complex bimanual–bipedal movements may accompany the impairment of consciousness, and running during seizures (termed cursive seizures) has been noted in some patients (Sher and Brown, 1976; Machado et al., 1991; Kuzniecky et al., 1997; Deonna and Ziegler, 2000). Focal motor features may include asymmetric tonic posturing, head version and/or eye deviation, unilateral or bilateral lower facial contraction, and occasionally clonic facial twitching or limb jerking. It is the automatisms and focal motor features which, in conjunction with regionalized or lateralized scalp EEG changes, may lead to the impression of temporal or frontal origin of seizures in patients with HH. It is likely that these clinical seizure characteristics represent spread of seizure activity from the HH to frontal and temporal cortex, though this has not been well studied. In our experience, lateralized motor features such as head version and tonic facial contraction usually correlate with the side of attachment of unilateral HH. As time passes, the laughter component may be lost, although parents often identify the habitual seizures as gelastic in the absence of laughter, perhaps because the accompanying facial distortion and prominent autonomic features are retained.
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In approximately 70% of patients in larger surgical series (Palmini et al., 2002; Harvey et al., 2003), there is further progression to SGE with patients having drop attacks, tonic and tonic–clonic seizures. Drop attacks can be of the atonic or tonic type. Tonic seizures may be preceded or accompanied by gelastic and complex features. In other patients, gelastic and complex partial seizures are followed by epileptic spasms (Striano et al., 1999; Freeman et al., 2003a). Tonic seizures or epileptic spasms may also be asymmetric, seemingly dependent on the side of predominant HH attachment. Such an epileptic progression heralds a significant deterioration and is the prompt for surgery in many children. The progression of seizures is usually paralleled by a progression in EEG abnormalities and neurobehavioral disturbance (Berkovic et al., 1988; Tassinari et al., 1997). The mechanism of this deterioration and its determinants are not known but may be due in part to secondary epileptogenesis (Freeman et al., 2003a). Rarely, patients can present in infancy with infantile spasms (Gomibuchi et al., 1990; Freeman et al., 2003a) or other myoclonic epilepsy and may not have had gelastic seizures, although these usually develop at a later date. Gelastic seizures are typically resistant to treatment with antiepileptic medication and in themselves can be intrusive and disabling. CPS and tonic seizures are similarly resistant to treatment in most patients, though antiepileptic medication may modify the severity or frequency of attacks. Results of vagal nerve stimulation and the ketogenic diet are similarly disappointing in the few reports of their use in patients with HH (Murphy et al., 2000; Harvey et al., 2003). Detailed history taking of seizures, particularly the evolution of complex partial and tonic seizures, is an important part of the evaluation. If secondary epileptogenesis is the basis of the epileptic progression, it is possible that seizure outcome after surgery may depend on the duration of SGE; in the RCH series, the presence of SGE was not predictive of (poorer) surgical outcome (Harvey et al., 2003). Video analysis of seizures from home recordings and video-EEG monitoring is equally important. However, the epileptologist needs to be mindful of the fact that seizure manifestations characteristic of frontal, temporal, and generalized seizures may be present, while gelastic seizures or gelastic features may have disappeared, in patients with HH when evaluated for surgery. In fact, very few clinical seizure characteristics would be inconsistent with HH seizure origin and spread: simple
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Fig. 2. Scalp EEG recordings in a 15-year-old girl with intellectual disability, intractable gelastic and complex partial seizures, and subclinical nocturnal tonic seizures. The interictal awake EEG (A) shows normal 9-Hz posterior alpha activity without epileptiform activity. The interictal sleep EEG (B) shows intermittent paroxysms of a generalized slow spike and wave at 2–2.5 Hz. The ictal EEG from sleep (C) shows periods of diffuse attenuation and generalized low-voltage fast activity without clinical change (arrow), then arousal from sleep (arrowhead) followed by sitting up in bed, looking around, and smiling. Frequent occurrence of these electrographic seizures, with and without clinical accompaniments, occurred throughout the night.
partial seizures with visual, somatosensory or experiential auras, or elementary motor features alone would certainly raise suspicion of neocortical seizure origin. 3.2. Interictal EEG Scalp EEG in patients with HH is variable, reflecting the age of the patient and the evolution of seizures (Fig. 2). In infants and children with only gelastic seizures, as well as in adults with a milder form of epilepsy, the interictal EEG is usually normal (Paillas et al., 1969; Machado et al., 1991; Sturm et al., 2000). The absence of interictal epileptiform activity on scalp EEG is often a factor in the late or missed diagnosis of the epileptic basis of the laughing attacks. Interictal EEG abnormalities may not appear until later childhood (Machado et al., 1991), coinciding with the appearance of CPS; increasing EEG abnormalities associated with clinical worsening of seizures are a common trend (Tassinari et al., 1997). Initially, the interictal record may be abnormal only during sleep (Cerullo et al., 1998), and we have also noted prominent sleep activation of EEG abnormalities in our patients. Sharp-slow and spike-slow wave activity ap-
pears particularly over the frontal and temporal regions and may be bilaterally synchronous or predominantly unilaterally distributed (Cascino et al., 1993; Tassinari et al., 1997); unilateral abnormalities tend to occur on the side of predominant HH attachment (unpublished observations). In patients with tonic and other generalized seizures, background slowing is common, and multifocal or generalized spike-wave activity is recorded, often with electrical spike-wave status in sleep. Furthermore, some patients have the typical EEG pattern of the Lennox–Gastaut syndrome, namely generalized slow spike-wave, paroxysmal fast activity and electrodecremental patterns (Freeman et al., 2003a). Such widespread epileptic activity was once thought to represent occult cerebral dysgenesis or irreversible “brain damage”, but as is the case in many childhood epilepsies where an epileptic encephalopathy exists with focal cortical malformations, such EEG activity seems to be a secondary or reactive phenomenon. In a surgical series of 12 patients with SGE, all had abundant interictal slow spike-wave on their preoperative EEG, but following successful surgery, there was a lasting reduction in interictal epileptiform activity, with waking spike-wave absent in 7 patients (60%)
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and markedly reduced in a further 2 (17%) (Freeman et al., 2003a). The origin of interictal spike-wave recorded on scalp EEG is an issue of some controversy. It is highly unlikely that an amorphous mass of nonlayered gray matter deep in the middle of the cranium would generate potentials of significant amplitude to be recorded on the scalp surface. In the RCH series of patients with HH and SGE, brief interictal recording at the time of HH resection revealed slow spike-wave activity over the frontal scalp bilaterally and over the exposed right frontal cortex before, during, and after HH resection, without interictal epileptiform activity recorded from within the HH. While interictal epileptiform activity has been recorded from HH in patients chronically implanted with depth electrodes, these discharges were not synchronous with, or related to, the more frequent discharges recorded from the cerebral cortex (Kahane et al., 1997). It is postulated that the spike-wave activity recorded at the scalp in patients with HH is likely generated in subcortical structures in response to frequent abnormal activity in the adjacent HH (Kahane et al., 1997); the process, akin to secondary epileptogenesis, may be dependent on anatomic connections of the hamartoma such as the mammillothalamic tract (Freeman et al., 2003a). We have performed spike-triggered functional MR imaging in a patient with a large HH and abundant, multifocal, and predominantly left-sided spike-wave on interictal EEG; the study showed changes related to spike-wave discharges in posterior cingulate cortex bilaterally and in the left frontal and temporal lobes, but not in the HH (unpublished observations). The epileptologist should not be dissuaded from a clinical diagnosis of epilepsy by the finding of a normal interictal (or ictal) EEG in a patient with gelastic episodes alone, particularly in an infant or young child and even when the events are very frequent. Conversely, in assessing suitability for epilepsy surgery, the epileptologist should not be alarmed by an interictal EEG showing focal, hemispheric, or generalized spike-wave and background abnormality, other than it potentially indicating a degree of progression of epileptogenesis. An attempt at quantitation of spike-wave activity is of potential interest in patients with cognitive or behavioral disturbance, particularly when compared with EEG after surgery, as almost continuous interictal EEG disturbance may be, in part, the basis of cognitive and behavioural problems. Asymmetry of EEG abnormalities is similarly of interest
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when considering asymmetric attachment of HH to the hypothalamus proper. 3.3. Ictal EEG monitoring, including intracranial recordings Ictal EEG recording of habitual seizures usually underpins the presurgical evaluation of patients with intractable epilepsy, in selected cases with EEG recording from the brain’s surface and depth. Gelastic epilepsy associated with HH poses a unique epilepsy surgery problem in that the lesion lies not within the cerebral cortex but in a subcortical location at the base of the brain, making EEG localization of seizures problematic. In patients with HH and brief gelastic seizures, scalp EEG may show no ictal change (Paillas et al., 1969). Later, as tonic seizures and interictal slow spike-wave develop, gelastic seizures are marked by suppression of the interictal discharges and attenuation of background rhythms, with or without widespread low-voltage fast activity (Berkovic et al., 1988). In patients with CPS and focal motor manifestations, ictal EEG recordings may show focal rhythms or spike-wave activity, either unilaterally or bilaterally. Apparent focal onset of seizures in the frontal or anterior temporal lobes of patients studied with intracranial EEG recordings (but without electrodes in the HH) once led to unsuccessful focal cortical resections in these patients with cortical pseudolocalization (Cascino et al., 1993). In tonic seizures or epileptic spasms, cessation of the interictal discharges is typically accompanied by either focal or generalized low-voltage fast activity or diffuse decremental patterns (Kahane et al., 1997). Thus, variable patterns of scalp ictal EEG are seen in patients with seizures and HH, none of which are specific for HH localization. Convincing demonstration of HH seizure origin was unavailable until depth EEG recordings from the HH were performed (Kahane et al., 1994, 1997, 1999; Munari et al., 1995; Kuzniecky et al., 1997). These showed that gelastic seizures were associated with an ictal discharge within in the HH that, in most cases, remained confined to the HH. In one case, electrodes also explored the adjacent anterior and posterior hypothalamus, but these were not involved by the seizure discharge; instead, the discharge spread to the anterior cingulate gyri (Munari et al., 1995). Electrical stimulation of the HH via the depth electrodes in these cases also provoked the characteristic ictal laughter.
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In contrast, recording of tonic seizures revealed discharges that always spared the hamartoma but involved various cortical areas (Kahane et al., 1997). In the large RCH series (Harvey et al., 2003) and French series (Delalande and Fohlen, 2003), none of the patients underwent chronic recording with intracranial EEG to document HH seizure origin, and only a minority of those surgical cases in the literature have been studied as such. 3.4. PET and ictal SPECT Functional imaging studies in patients with HH and seizures are few. Positron emission tomography (PET) studies are scarce and report either scattered areas of cortical hypometabolism (Kitajima et al., 1998) or regional hypometabolism, the lateralization of which is concordant with asymmetric HH attachment (Palmini
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et al., 2002). SPECT studies have been performed more often (Acilona Echeverria et al., 1994; Kuzniecky et al., 1997, 2001; DiFazio and Davis, 2000; Khadilkar et al., 2001) and, in the RCH series, were pivotal in leading to surgery in our first operated patients (Harvey et al., 1998). Several authors have reported patients in whom injection of radioisotope during gelastic seizures demonstrated focal hyperperfusion in the region of the HH (Kuzniecky et al., 1997, 2001; Harvey et al., 1998; DiFazio and Davis, 2000). In the RCH series of 20 patients studied with subtraction ictal-interictal SPECT, 13 showed significant HH hyperperfusion, and ictal laughter was predictive of this (unpublished observations). In addition to HH hyperperfusion, asymmetric ictal (and less frequently interictal) rCBF patterns were seen, with abnormalities usually ipsilateral to the side of predominant HH attachment, perhaps suggesting preferential spread (Fig. 3).
Fig. 3. Coregistered axial (top row), sagittal (middle row), and coronal (bottom row) SPECT images of regional cerebral blood flow in a 13-year-old girl with a large hypothalamic hamartoma and refractory gelastic seizures. Ictal SPECT (left column), interictal SPECT (second column), subtraction interictal from ictal SPECT (third column), and subtraction SPECT overlaid on MRI (right column) are shown following coregistration of SPECT and MRI data sets and slicing in identical planes and positions. The ictal SPECT study was obtained following injection of Tc-99m-HMPAO 19 s after cessation of a typical gelastic seizure of 64-s duration. Ictal hyperperfusion is demonstrated in the hypothalamic hamartoma.
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4. Summary Historically, the findings of interictal and ictal EEG recordings in patients with HH, both with scalp and intracranial electrodes, led to the incorrect assumptions that seizures arose in the cerebral cortex, that the HH simply an epiphenomenon in a more widespread but occult cerebral dysplasia, and that in patients with SGE, there was either diffuse dysgenesis or irreversible brain damage. It was not until the results of depth electrode EEG recordings and ictal SPECT studies were reported, and the benefits of HH resection were realized, that the concept of HH seizure origin became accepted. While the mechanisms of spike-wave generation, tonic seizure evolution, and cognitive deterioration remain elusive in this syndrome, there is now acceptance of a pivotal role of the intrinsically epileptogenic HH, with potential for improved seizure control, behavior, and cognition with its resection or disconnection. As previously stated, the most important aspects of the preoperative evaluation are assessments of endocrine status, cognition and behavior, seizure and EEG evolution, and HH anatomical characteristics. Ictal EEG recordings, SPECT studies, and intracranial EEG are probably of limited value in the preoperative investigation of patients with HH, and may potentially lead the epileptologist to believe that seizures do not originate in the HH and that HH resection is not indicated. Ictal EEG recordings and SPECT studies might play a role in excluding a neocortical focus, but there is a great risk of seeing erroneous, pseudolocalization. A careful review of a high-quality MRI and attention to seizure manifestations is more likely to better exclude another source of seizures. Depth EEG recordings need only be considered if there is definite, additional pathology on MR imaging, and seizure localization is not apparent from the noninvasive evaluation. References Acilona Echeverria, V, Casado Chocan, JL, Lopez Dominguez, JM, Aguilera Navarro, JM, Marques, ME and Munoz, VC (1994) Gelastic seizures, precocious puberty and hypothalamic hamartomas. A case report and the contributions of Single Photon Emission Computed Tomography (SPECT). Neurologia, 9: 61–64. Arita, K, Ikawa, F, Kurisu, K, Sumida, M, Harada, K, Uozumi, T, Monden, S, Yoshida, J and Nishi, Y (1999) The relationship between magnetic resonance imaging
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findings and clinical manifestations of hypothalamic hamartoma. J. Neurosurg., 91: 212–220. Arroyo, S, Lesser, RP, Gordon, B, Uematsu, S, Hart, J, Schwerdt, P, Andreasson, K and Fisher, RS (1993) Mirth, laughter and gelastic seizures. Brain, 116(Pt 4): 757–780. Berkovic, SF, Andermann, F, Melanson, D, Ethier, RE, Feindel, W and Gloor, P (1988) Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging. Ann. Neurol., 23: 429–439. Berkovic, SF, Kuzniecky, RI and Andermann, F (1997) Human epileptogenesis and hypothalamic hamartomas: new lessons from an experiment of nature. Epilepsia, 38: 1–3. Biraben, A, Sartori, E, Taussig, D, Bernard, AM and Scarabin, JM (1999) Gelastic seizures: video–EEG and scintigraphic analysis of a case with a frontal focus; review of the literature and pathophysiological hypotheses. Epileptic Disord., 1: 221–227. Boyko, OB, Curnes, JT, Oakes, WJ and Burger, PC (1991) Hamartomas of the tuber cinereum: CT, MR, and pathologic findings. Am. J. Neuroradiol., 12: 309–314. Breningstall, GN (1985) Gelastic seizures, precocious puberty, and hypothalamic hamartoma. Neurology, 35: 1180–1183. Cascino, GD, Andermann, F, Berkovic, SF, Kuzniecky, RI, Sharbrough, FW, Keene, DL, Bladin, PF, Kelly, PJ, Olivier, A and Feindel, W (1993) Gelastic seizures and hypothalamic hamartomas: evaluation of patients undergoing chronic intracranial EEG monitoring and outcome of surgical treatment. Neurology, 43: 747–750. Cerullo, A, Tinuper, P, Provini, F, Contin, M, Rosati, A, Marini, C and Cortelli, P (1998) Autonomic and hormonal ictal changes in gelastic seizures from hypothalamic hamartomas. Electroencephalogr. Clin. Neurophysiol., 107: 317–322. Chen, RC and Forster, FM (1973) Cursive epilepsy and gelastic epilepsy. Neurology, 23: 1019–1029. Delalande, O and Fohlen, M (2003) Disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification. Neurol. Med. Chir. (Tokyo), 43: 61–68. Deonna, T and Ziegler, AL (2000) Hypothalamic hamartoma, precocious puberty and gelastic seizures: a special model of “epileptic” developmental disorder. Epileptic Disord., 2: 33–37. Diebler, C and Ponsot, G (1983) Hamartomas of the tuber cinereum. Neuroradiology, 25: 93–101. DiFazio, MP and Davis, RG (2000) Utility of early single photon emission computed tomography (SPECT) in neonatal gelastic epilepsy associated with hypothalamic hamartoma. J. Child Neurol., 15: 414–417. Druckman, R and Chao, D (1955) Massive spasms in infancy and childhood. Epilepsia, 4: 61–72.
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Druckman, R and Chao, D (1957) Laughter in epilepsy. Neurology, 7: 26–36. Dunoyer, C, Ragheb, J, Resnick, T, Alvarez, L, Jayakar, P, Altman, N, Wolf, A and Duchowny, M (2002) The use of stereotactic radiosurgery to treat intractable childhood partial epilepsy. Epilepsia, 43: 292–300. Foerster, O and Gagel, O (1933) Ein Fall von Ependymcyste des III. Ventrikels. Ein Beitrag zur Frage der Beziehungen psychischer St¨orungen zum Hirnstamm. Z. ges. Neurol. Psychiatr., 149: 312–344. Freeman, JL, Harvey, AS, Rosenfeld, JV, Wrennall, J, Bailey, CA and Berkovic, SF (2003a) Generalized epilepsy in hypothalamic hamartoma: evolution and postoperative resolution. Neurology, 60: 762–767. Freeman, JL, Zacharin, M, Rosenfeld, JV and Harvey, AS (2003) The endocrinology of hypothalamic hamartoma surgery for intractable epilepsy. Epileptic Disord, 5: 239–247. Freeman, JL, Coleman, LT, Wellard, RM, Ke, MJ, Rosenfeld, JV, Jackson, GD, Berkovic, SF, and Harvey, AS (2004) MR imaging and spectroscopic study of epileptogenic hypothalamic hamartomas: analysis of 72 cases. Am. J. Neuroradiol., 25: (in press). Fukuda, M, Kameyama, S, Wachi, M and Tanaka, R (1999) Stereotaxy for hypothalamic hamartoma with intractable gelastic seizures: technical case report. Neurosurgery, 44: 1347–1350. Gascon, GG and Lombroso, CT (1971) Epileptic (gelastic) laughter. Epilepsia, 12: 63–76. Gomibuchi, K, Ochiai, Y, Kanraku, S and Maekawa, K (1990) Infantile spasms and gelastic seizure due to hypothalamic hamartoma. No To Hattatsu, 22: 392–394. Harvey, AS, Rosenfeld, JV and Wrennall, J (1998) Hypothalamic hamartoma and intractable epilepsy: ictal SPECT localization and surgical resection of hamartoma in four children. Epilepsia, 39: S65. Harvey, AS, Freeman, JL, Berkovic, SF and Rosenfeld, JV (2003) Transcallosal resection of hypothalamic hamartomas in patients with intractable epilepsy. Epileptic Disord., 5: 257–265. Kahane, P, Tassi, L, Hoffmann, D, Francione, S, GratadouJuery, G, Pasquier, B and Munari, C (1994) Crises dacrystiques et hamartome hypothalamique. A propos d’une observation vid´eo-st´er´eo-EEG. Epilepsies, 6: 259–279. Kahane, P, Munari, C, Minotti, L, Hoffman, D, Tassi, L, Pasquier, B, Grand, S and Benabid, AL (1997) The role of the hypothalamic hamartoma in the genesis of gelastic and dacrystic seizures. In: I Tuxhorn, H Hothausen and H Boenigk (Eds.), Paediatric Epilepsy Syndromes and their Surgical Treatment. John Libbey, London, pp. 447–461. Kahane, P, Di, Leo, M, Hoffmann, D and Munari, C (1999) Ictal bradycardia in a patient with a hypothalamic hamartoma: a stereo-EEG study. Epilepsia, 40: 522–527.
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Khadilkar, S, Menezes, K, Lele, V and Katrak, S (2001) Gelastic epilepsy – a case report with SPECT studies. J. Assoc. Physicians India, 49: 581–583. Kitajima, K, Ikeda, A, Terada, K, Shibasaki, H and Kimura, J (1998) A case of hypothalamic hamartoma manifesting gelastic seizure and multifocal independent seizure foci. Rinsho Shinkeigaku, 38: 305–310. Kuzniecky, R, Guthrie, B, Mountz, J, Bebin, M, Faught, E, Gilliam, F and Liu, HG (1997) Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy. Ann. Neurol., 42: 60–67. Kuzniecky, RI, Knowlton, R, Lawn, N, Mountz, J and Faught, E (2001) Ictal single-photon emission computed tomography (SPECT) findings in hypothalamic hamartomas and intractable seizures. Epilepsia, 42: S101. Kuzniecky, R, Guthrie, B, Knowlton, R, Faught, E and Backensto, E (2002) Minimally invasive surgical management of hypothalamic hamartomas in gelastic epilepsy. Epilepsia, 43(Suppl. 7): 348. List, CF, Dowman, CE, Bagchi, BK and Bebin, J (1958) Posterior hypothalamic hamartomas and gangliogliomas causing precocious puberty. Neurology, 8: 164–174. Loiseau, P, Cohadon, F and Cohadon, S (1971) Gelastic epilepsy. A review and report of five cases. Epilepsia, 12: 313–323. Machado, HR, Hoffman, HJ and Hwang, PA (1991) Gelastic seizures treated by resection of a hypothalamic hamartoma. Childs Nerv. Syst., 7: 462–465. Martin, JP (1950) Fits of laughter (sham mirth) in organic cerebral disease. Brain, 73: 453–464. Munari, C, Kahane, P, Francione, S, Hoffmann, D, Tassi, L, Cusmai, R, Vigevano, F, Pasquier, B and Betti, OO (1995) Role of the hypothalamic hamartoma in the genesis of gelastic fits (a video-stereo-EEG study). Electroencephalogr. Clin. Neurophysiol., 95: 154–160. Murphy, JV, Wheless, JW and Schmoll, CM (2000) Left vagal nerve stimulation in six patients with hypothalamic hamartomas. Pediatr. Neurol., 23: 167–168. Paillas, JE, Roger, J, Toga, M, Soulayrol, R, Salamon, G, Dravet, C and Bureau, M (1969) Hamartome de l’hypothalmus: e´ tude clinique, radiologique, histologique: r´esultats de l’ex`er`ese. Rev. Neurol. (Paris), 120: 177–194. Palmini, A, Chandler, C, Andermann, F, Costa, DC, PaglioliNeto, E, Polkey, C, Rosenblatt, B, Montes, J, Martinez, JV, Farmer, JP, Sinclair, B, Aronyk, K, Paglioli, E, Coutinho, L, Raupp, S and Portuguez, M (2002) Resection of the lesion in patients with hypothalamic hamartomas and catastrophic epilepsy. Neurology, 58: 1338–1347. Parrent, AG (1999) Stereotactic radiofrequency ablation for the treatment of gelastic seizures associated with hypothalamic hamartoma. Case report. J. Neurosurg., 91: 881–884.
450 Pendl, G (1975) Gelastic epilepsy in tumours of the hypothalamic region. Adv. Neurosurg., 3: 442–449. Regis, J, de Bartolomei, F, Toffol, B, Genton, P, Kobayashi, T, Mori, Y, Takakura, K, Hori, T, Inoue, H, Schrottner, O, Pendl, G, Wolf, A, Arita, K and Chauvel, P (2000) Gamma knife surgery for epilepsy related to hypothalamic hamartomas. Neurosurgery, 47: 1343–1351. Rosenfeld, JV, Harvey, AS, Wrennall, J, Zacharin, M and Berkovic, SF (2001) Transcallosal resection of hypothalamic hamartomas, with control of seizures, in children with gelastic epilepsy. Neurosurgery, 48: 108–118. Sher, PK and Brown, SB (1976) Gelastic epilepsy. Onset in neonatal period. Am. J. Dis. Child., 130: 1126–1131. Striano, S, Meo, R, Bilo, L, Cirillo, S, Nocerino, C, Ruosi, P, Striano, P and Estraneo, A (1999) Gelastic epilepsy:
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symptomatic and cryptogenic cases. Epilepsia, 40: 294–302. Sturm, JW, Andermann, F and Berkovic, SF (2000) “Pressure to laugh”: an unusual epileptic symptom associated with small hypothalamic hamartomas. Neurology, 54: 971–973. Tassinari, CA, Riguzzi, P, Rizzi, R, Passarelli, D and Volpi, L (1997) Gelastic seizures. In: I Tuxhorn, H Hothausen and H Boenigk (Eds.), Paediatric Epilepsy Syndromes and their Surgical Treatment. John Libbey, London, pp. 429–446. Valdueza, JM, Cristante, L, Dammann, O, Bentele, K, Vortmeyer, A, Saeger, W, Padberg, B, Freitag, J and Herrmann, HD (1994) Hypothalamic hamartomas: with special reference to gelastic epilepsy and surgery. Neurosurgery, 34: 949–958.
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CHAPTER 3.7
Presurgical evaluation in patients with hypothalamic hamartomas A.S. Harveya,b,c,d,∗ , J.L. Freemanb,c,e and S.F. Berkovica,b,d,f a
Children’s Epilepsy Program, Royal Children’s Hospital, Melbourne, Australia b Comprehensive Epilepsy Programme, Austin Health, Melbourne, Australia c Department of Paediatrics, University of Melbourne, Melbourne, Australia d Epilepsy Research Collaborative Centre, University of Melbourne, Melbourne, Australia e Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia f Department of Medicine, University of Melbourne, Melbourne, Australia
1. Introduction Hypothalamic hamartomas (HH) are a rare brain malformation comprising a tumor-like mass of neuronal and glial tissue in the suprasellar region, typically attached to the mamillary bodies on one or both sides and extending antero-inferiorly from the tuber cinereum, with or without extension into the third ventricle above (Boyko et al., 1991). HH characteristically present with seizures, precocious puberty, or both (Diebler and Ponsot, 1983), although the relative incidence of their neurological and endocrinological manifestations is unknown (List et al., 1958). Seizures typically have their onset in infancy or early childhood and, with rare exceptions, are gelastic (laughing) and/or dacrystic (crying) in nature (Tassinari et al., 1997). The epilepsy associated with HH is usually resistant to treatment with antiepileptic medication and in many patients evolves to a symptomatic generalized epilepsy (SGE) with tonic–clonic seizures and drop attacks, often accompanied by neurobehavioral deterioration with intellectual disability and bouts of rage and aggression (Berkovic et al., 1988; Tassinari et al., 1997). A small number of patients have a milder form of epilepsy associated with normal intelligence, an aura described as “pressure to laugh”, infrequent gelastic seizures and rare complex partial or focal motor seizures (Sturm et al., 2000). ∗
Correspondence to: Dr. A. Simon Harvey, Epileptologist. Director, Children’s Epilepsy Program, Royal Children’s Hospital, Parkville, Melbourne, Australia 3052. E-mail address: [email protected] Tel.: +61-3-9345-5661; fax: +61-3-9345-5977.
HH associated with seizures usually have an intraventricular component and sessile attachment to the hypothalamus, whereas those associated with precocious puberty alone are either pedunculated in their attachment or do not distort the hypothalamus and third ventricular outline (Valdueza et al., 1994; Arita et al., 1999; Freeman et al., 2004). The basis of the seizure disorder seems to be an intrinsic epileptogenicity (Berkovic et al., 1997; Kuzniecky et al., 1997), and much of the electroclinical expression may be mediated by connections of the hamartoma or adjacent hypothalamus (Kahane et al., 1997; Freeman et al., 2003a). However, the considerable variability in seizure, cognitive and behavioral manifestations in patients with HH is largely unexplained and seems not to be due to differences in HH size and attachment. 2. Epilepsy surgery for hypothalamic hamartoma Given the often severe, refractory, and sometimes progressive nature of the epilepsy associated with HH, various surgical approaches have been employed to treat the seizures. Prior to the acceptance of HH origin of seizures in this syndrome, some patients underwent anterior temporal or frontal lobe resections due to pseudolocalization of seizures to these cortical regions, the results of which were universally disappointing (Cascino et al., 1993). Over the years, case reports of patients with refractory epilepsy treated with resection or disconnection of their HH have been published, the results being variable but encouraging. More recently, several groups have reported experience with larger numbers of patients treated with resection of the HH, employing various approaches. Classical
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subfrontal or transsylvian approaches to the HH from below have been most commonly employed, with a significant proportion of patients having residual lesion and postoperative seizures, and many suffering complications such as stroke, cranial neuropathy, or endocrine disturbance (Palmini et al., 2002). Delalande recently reported open and endoscopic approaches to disconnection of HH, with good seizure outcome and fewer operative complications than with pterional resection (Delalande and Fohlen, 2003). Our group has employed a transcallosal approach to resection of HH, this approach providing better access to the lesion and greater ability to resect what we believe to be the crucial component of the HH, that being the intraventricular component attached to the mammillary bodies (Rosenfeld et al., 2001). Results from surgery in over 29 children at our center indicate that approximately 50% are seizure-free, and most of the remainder have had worthwhile seizure reduction; furthermore, improvements in language, schooling, and behavior are almost universal in our operated patients, and neither permanent neurological nor significant endocrine disturbance have occurred (Freeman et al., 2003b; Harvey et al., 2003). This approach has also been employed in 6 adult patients (aged 20–33 years), with seizure improvement seen in all but 1 during limited follow-up (unpublished observations). Stereotactic radiosurgery with the gamma knife is reported to be successful in a similar proportion of patients (Regis et al., 2000; Dunoyer et al., 2002), with the suggestion that subnecrotic doses of radiation to the HH only are required. Radiofrequency thermocoagulation (Kuzniecky et al., 1997; Fukuda et al., 1999; Parrent, 1999) and endoscopic removal (Kuzniecky et al., 2002) are also reported. Presently, debate exists about the most effective and safest neurosurgical approach to these lesions, the selection of patients, the timing of surgery, and the long-term outcome following surgery.
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sis on proof of seizure localization to the lesion. The key elements of the presurgical investigation of patients with HH can be summarized as follows:
• Assessment of the patient’s epilepsy with regard to
•
•
3. Preoperative investigation of hypothalamic hamartoma
• The investigation of patients with HH for potential epilepsy surgery, regardless of the operative approach employed, is similar to the investigation of patients with refractory epilepsy due to cerebral lesions. However, there are some important differences, including (1) the need for perioperative endocrine assessment; (2) the need for precise anatomical imaging of the midline structures of the brain; and (3) perhaps less empha-
seizure evolution over time, the likelihood of seizure origin in the HH, and the impact of seizures on the patient’s life. This is done with a detailed seizure history, routine scalp EEG, video–EEG monitoring, ictal single-photon emission computed tomography (SPECT), and intracranial EEG recording. The application of these modalities to the investigation of patients with HH is discussed in detail below. Characterization of the patient’s cognitive, behavioral, and psychiatric status, in particular the degree of any memory disturbance, intellectual disability, and episodic rage. This is generally done with a detailed developmental history, neuropsychological testing, and psychiatric evaluation. These aspects of the presurgical evaluation are not discussed here. Demonstration of the HH size, signal characteristics, attachment, lateralization, and relationship to normal structures (e.g. mamillary bodies, fornices, mamillothalamic tracts, hypothalamic nuclei), as well as exclusion of other potentially epileptogenic lesions such as cortical dysplasia. This is achieved with high-resolution magnetic resonance imaging (MRI) employing standard epilepsy protocols supplemented by thin T2-weighted slices in the three orthogonal planes through the HH and adjacent midline structures. The T2-weighted sequences are particularly important to provide maximum signal contrast between the hypothalamic nuclei (normal gray signal), the HH (usually high signal), and the heavily myelinated fornices, mammillary bodies, and mammillothalamic tracts (low signal). This aspect of the presurgical evaluation is particularly important in the assessment of surgical candidacy, the choice and planning of the surgical approach, and the postoperative assessment. MRI evaluation of HH is not discussed further here. Characterization of baseline endocrine status and reassessment following surgery is a crucial aspect of the perioperative management of all patients with HH, not only those with precocious puberty. Clinical and biochemical assessments of growth, thyroid, adrenal, and sexual function, as well as water balance and appetite, are obtained by clinical examination, hormone assays, and stimulation tests, not discussed further here.
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Fig. 1. Schematic representation of the age-related transition from gelastic to partial to tonic seizures that occurs in many patients with hypothalamic hamartoma and intractable epilepsy coming to presurgical evaluation. Gelastic features may persist as isolated gelastic seizures, be incorporated in partial and tonic seizures, or be replaced during this evolution.
The review that follows is concentrated on aspects of seizure analysis in HH with clinical, EEG, and SPECT modalities. Presurgical evaluation of endocrine status and MR imaging of HH are reviewed elsewhere (Freeman et al., 2003b; Freeman et al., 2004). 3.1. Seizure history and video analysis The epileptic syndrome in patients with HH is quite stereotyped, with gelastic (laughing) or dacrystic (crying) seizures almost universal. Variability in the age at seizure onset, frequency and severity of seizures, and degree of evolution to complex partial seizures (CPS) and to SGE accounts for most differences between patients (Fig. 1). Most patients presenting for surgery are children with multiple daily gelastic, complex partial and tonic seizures, many having a Lennox–Gastaut syndrome. In the RCH series of 29 patients, 2 had gelastic seizures only, 27 had CPS, and 22 had secondary generalized or tonic seizures (Harvey et al., 2003). Gelastic seizures are reported as beginning in the first year of life in over a third of patients (Tassinari et al., 1997); neonatal onset is common, and onset from the first day of life is well known (Sher and Brown, 1976; Diebler and Ponsot, 1983; Berkovic et al., 1988; Kuzniecky et al., 1997; DiFazio and Davis, 2000; Palmini et al., 2002; Freeman et al., 2003a). The seizures are stereotypical with bouts of laughter-like vocalization, associated with unilateral or bilateral facial contraction in the guise of a smile (Pendl, 1975) and with autonomic disturbance such as flushing, tachycardia, and modified respiration (Cerullo et al., 1998). In some patients, the sound produced has a crying quality, and the facial contraction mimics a grimace. There may also be a combination of gelastic and dacrystic seizures in the same patient (Breningstall, 1985) and in the same seizure (Kahane et al., 1997).
Older patients do not report a feeling of humour, and in fact, many report the feeling as unpleasant, or associated with epigastric or other discomfort (Striano et al., 1999). When assessable, the conscious state may not be impaired. In its mildest form, patients may simply report an urge to laugh that can be suppressed (Sturm et al., 2000). Gelastic seizures can occur with a very high frequency and periodicity, particularly in infants, and they often occur from sleep. Gelastic seizures are rarely diagnosed at onset. They may be mistaken for normal laughter, as in the case of one child who won a happy baby contest (Berkovic et al., 1988), or misdiagnosed as infantile colic. The presentation of gelastic seizures in early infancy illustrates the importance of parental interpretation of the vocalization and facial contraction in determining whether they are ultimately labeled as either gelastic or dacrystic; laughter in the neonatal period is developmentally precocious, raising the question of whether this is an appropriate description of the seizures (Berkovic et al., 1988). While the neuroanatomical basis of ictal laugher in patients with HH is not entirely known, there are reasons to suspect that electrical stimulation of the adjacent hypothalamus by the hamartoma is responsible. Mechanical stimulation of the floor of the third ventricle, for example, has been shown to induce laughter (Foerster and Gagel, 1933), as has acute subarachnoid hemorrhage adjacent to the mammillary bodies (Martin, 1950). Discussed in more detail below, stereotactic depth electrode encephalography has demonstrated origin of gelastic seizures within HH, but the seizure discharge remained confined to the HH in most cases, without involvement of the adjacent anterior and posterior hypothalamus where this could be determined (Munari et al., 1995). It should be remembered that laughter may be seen in patients with complex partial seizures of temporal and frontal origin (Arroyo et al., 1993; Biraben et al., 1999), in
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association with infantile spasms (Druckman and Chao, 1955; Druckman and Chao, 1957), and in metabolic and other degenerative diseases (Chen and Forster, 1973). The laughter associated with HH is often said to have a mechanical or unnatural quality, and it was previously proposed that the nature of the laughter might enable distinction between gelastic seizures of diencephalic and temporal origin (Gascon and Lombroso, 1971). In our experience, however, this is not so; laughter without an affective component may occur in temporal lobe seizures (Loiseau et al., 1971), and we have observed laughter in several of our HH patients that is both mirthful and has an infectious quality. Patients with HH may continue to have only gelastic seizures, but in many, there is progression during midchildhood to complex partial seizures. It is often this progression that alerts parents and physicians to the epileptic nature of the laughter attacks. CPS in patients with HH typically manifest as behavioral arrest and staring, often with preceding or accompanying laughter and autonomic disturbance. Epigastric discomfort and fear may be present, as in typical mesial temporal lobe epilepsy, but experiential and psychic phenomena are rare. Simple gestural and oroalimentary automatisms, axial movements, and complex bimanual–bipedal movements may accompany the impairment of consciousness, and running during seizures (termed cursive seizures) has been noted in some patients (Sher and Brown, 1976; Machado et al., 1991; Kuzniecky et al., 1997; Deonna and Ziegler, 2000). Focal motor features may include asymmetric tonic posturing, head version and/or eye deviation, unilateral or bilateral lower facial contraction, and occasionally clonic facial twitching or limb jerking. It is the automatisms and focal motor features which, in conjunction with regionalized or lateralized scalp EEG changes, may lead to the impression of temporal or frontal origin of seizures in patients with HH. It is likely that these clinical seizure characteristics represent spread of seizure activity from the HH to frontal and temporal cortex, though this has not been well studied. In our experience, lateralized motor features such as head version and tonic facial contraction usually correlate with the side of attachment of unilateral HH. As time passes, the laughter component may be lost, although parents often identify the habitual seizures as gelastic in the absence of laughter, perhaps because the accompanying facial distortion and prominent autonomic features are retained.
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In approximately 70% of patients in larger surgical series (Palmini et al., 2002; Harvey et al., 2003), there is further progression to SGE with patients having drop attacks, tonic and tonic–clonic seizures. Drop attacks can be of the atonic or tonic type. Tonic seizures may be preceded or accompanied by gelastic and complex features. In other patients, gelastic and complex partial seizures are followed by epileptic spasms (Striano et al., 1999; Freeman et al., 2003a). Tonic seizures or epileptic spasms may also be asymmetric, seemingly dependent on the side of predominant HH attachment. Such an epileptic progression heralds a significant deterioration and is the prompt for surgery in many children. The progression of seizures is usually paralleled by a progression in EEG abnormalities and neurobehavioral disturbance (Berkovic et al., 1988; Tassinari et al., 1997). The mechanism of this deterioration and its determinants are not known but may be due in part to secondary epileptogenesis (Freeman et al., 2003a). Rarely, patients can present in infancy with infantile spasms (Gomibuchi et al., 1990; Freeman et al., 2003a) or other myoclonic epilepsy and may not have had gelastic seizures, although these usually develop at a later date. Gelastic seizures are typically resistant to treatment with antiepileptic medication and in themselves can be intrusive and disabling. CPS and tonic seizures are similarly resistant to treatment in most patients, though antiepileptic medication may modify the severity or frequency of attacks. Results of vagal nerve stimulation and the ketogenic diet are similarly disappointing in the few reports of their use in patients with HH (Murphy et al., 2000; Harvey et al., 2003). Detailed history taking of seizures, particularly the evolution of complex partial and tonic seizures, is an important part of the evaluation. If secondary epileptogenesis is the basis of the epileptic progression, it is possible that seizure outcome after surgery may depend on the duration of SGE; in the RCH series, the presence of SGE was not predictive of (poorer) surgical outcome (Harvey et al., 2003). Video analysis of seizures from home recordings and video-EEG monitoring is equally important. However, the epileptologist needs to be mindful of the fact that seizure manifestations characteristic of frontal, temporal, and generalized seizures may be present, while gelastic seizures or gelastic features may have disappeared, in patients with HH when evaluated for surgery. In fact, very few clinical seizure characteristics would be inconsistent with HH seizure origin and spread: simple
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Fig. 2. Scalp EEG recordings in a 15-year-old girl with intellectual disability, intractable gelastic and complex partial seizures, and subclinical nocturnal tonic seizures. The interictal awake EEG (A) shows normal 9-Hz posterior alpha activity without epileptiform activity. The interictal sleep EEG (B) shows intermittent paroxysms of a generalized slow spike and wave at 2–2.5 Hz. The ictal EEG from sleep (C) shows periods of diffuse attenuation and generalized low-voltage fast activity without clinical change (arrow), then arousal from sleep (arrowhead) followed by sitting up in bed, looking around, and smiling. Frequent occurrence of these electrographic seizures, with and without clinical accompaniments, occurred throughout the night.
partial seizures with visual, somatosensory or experiential auras, or elementary motor features alone would certainly raise suspicion of neocortical seizure origin. 3.2. Interictal EEG Scalp EEG in patients with HH is variable, reflecting the age of the patient and the evolution of seizures (Fig. 2). In infants and children with only gelastic seizures, as well as in adults with a milder form of epilepsy, the interictal EEG is usually normal (Paillas et al., 1969; Machado et al., 1991; Sturm et al., 2000). The absence of interictal epileptiform activity on scalp EEG is often a factor in the late or missed diagnosis of the epileptic basis of the laughing attacks. Interictal EEG abnormalities may not appear until later childhood (Machado et al., 1991), coinciding with the appearance of CPS; increasing EEG abnormalities associated with clinical worsening of seizures are a common trend (Tassinari et al., 1997). Initially, the interictal record may be abnormal only during sleep (Cerullo et al., 1998), and we have also noted prominent sleep activation of EEG abnormalities in our patients. Sharp-slow and spike-slow wave activity ap-
pears particularly over the frontal and temporal regions and may be bilaterally synchronous or predominantly unilaterally distributed (Cascino et al., 1993; Tassinari et al., 1997); unilateral abnormalities tend to occur on the side of predominant HH attachment (unpublished observations). In patients with tonic and other generalized seizures, background slowing is common, and multifocal or generalized spike-wave activity is recorded, often with electrical spike-wave status in sleep. Furthermore, some patients have the typical EEG pattern of the Lennox–Gastaut syndrome, namely generalized slow spike-wave, paroxysmal fast activity and electrodecremental patterns (Freeman et al., 2003a). Such widespread epileptic activity was once thought to represent occult cerebral dysgenesis or irreversible “brain damage”, but as is the case in many childhood epilepsies where an epileptic encephalopathy exists with focal cortical malformations, such EEG activity seems to be a secondary or reactive phenomenon. In a surgical series of 12 patients with SGE, all had abundant interictal slow spike-wave on their preoperative EEG, but following successful surgery, there was a lasting reduction in interictal epileptiform activity, with waking spike-wave absent in 7 patients (60%)
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and markedly reduced in a further 2 (17%) (Freeman et al., 2003a). The origin of interictal spike-wave recorded on scalp EEG is an issue of some controversy. It is highly unlikely that an amorphous mass of nonlayered gray matter deep in the middle of the cranium would generate potentials of significant amplitude to be recorded on the scalp surface. In the RCH series of patients with HH and SGE, brief interictal recording at the time of HH resection revealed slow spike-wave activity over the frontal scalp bilaterally and over the exposed right frontal cortex before, during, and after HH resection, without interictal epileptiform activity recorded from within the HH. While interictal epileptiform activity has been recorded from HH in patients chronically implanted with depth electrodes, these discharges were not synchronous with, or related to, the more frequent discharges recorded from the cerebral cortex (Kahane et al., 1997). It is postulated that the spike-wave activity recorded at the scalp in patients with HH is likely generated in subcortical structures in response to frequent abnormal activity in the adjacent HH (Kahane et al., 1997); the process, akin to secondary epileptogenesis, may be dependent on anatomic connections of the hamartoma such as the mammillothalamic tract (Freeman et al., 2003a). We have performed spike-triggered functional MR imaging in a patient with a large HH and abundant, multifocal, and predominantly left-sided spike-wave on interictal EEG; the study showed changes related to spike-wave discharges in posterior cingulate cortex bilaterally and in the left frontal and temporal lobes, but not in the HH (unpublished observations). The epileptologist should not be dissuaded from a clinical diagnosis of epilepsy by the finding of a normal interictal (or ictal) EEG in a patient with gelastic episodes alone, particularly in an infant or young child and even when the events are very frequent. Conversely, in assessing suitability for epilepsy surgery, the epileptologist should not be alarmed by an interictal EEG showing focal, hemispheric, or generalized spike-wave and background abnormality, other than it potentially indicating a degree of progression of epileptogenesis. An attempt at quantitation of spike-wave activity is of potential interest in patients with cognitive or behavioral disturbance, particularly when compared with EEG after surgery, as almost continuous interictal EEG disturbance may be, in part, the basis of cognitive and behavioural problems. Asymmetry of EEG abnormalities is similarly of interest
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when considering asymmetric attachment of HH to the hypothalamus proper. 3.3. Ictal EEG monitoring, including intracranial recordings Ictal EEG recording of habitual seizures usually underpins the presurgical evaluation of patients with intractable epilepsy, in selected cases with EEG recording from the brain’s surface and depth. Gelastic epilepsy associated with HH poses a unique epilepsy surgery problem in that the lesion lies not within the cerebral cortex but in a subcortical location at the base of the brain, making EEG localization of seizures problematic. In patients with HH and brief gelastic seizures, scalp EEG may show no ictal change (Paillas et al., 1969). Later, as tonic seizures and interictal slow spike-wave develop, gelastic seizures are marked by suppression of the interictal discharges and attenuation of background rhythms, with or without widespread low-voltage fast activity (Berkovic et al., 1988). In patients with CPS and focal motor manifestations, ictal EEG recordings may show focal rhythms or spike-wave activity, either unilaterally or bilaterally. Apparent focal onset of seizures in the frontal or anterior temporal lobes of patients studied with intracranial EEG recordings (but without electrodes in the HH) once led to unsuccessful focal cortical resections in these patients with cortical pseudolocalization (Cascino et al., 1993). In tonic seizures or epileptic spasms, cessation of the interictal discharges is typically accompanied by either focal or generalized low-voltage fast activity or diffuse decremental patterns (Kahane et al., 1997). Thus, variable patterns of scalp ictal EEG are seen in patients with seizures and HH, none of which are specific for HH localization. Convincing demonstration of HH seizure origin was unavailable until depth EEG recordings from the HH were performed (Kahane et al., 1994, 1997, 1999; Munari et al., 1995; Kuzniecky et al., 1997). These showed that gelastic seizures were associated with an ictal discharge within in the HH that, in most cases, remained confined to the HH. In one case, electrodes also explored the adjacent anterior and posterior hypothalamus, but these were not involved by the seizure discharge; instead, the discharge spread to the anterior cingulate gyri (Munari et al., 1995). Electrical stimulation of the HH via the depth electrodes in these cases also provoked the characteristic ictal laughter.
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In contrast, recording of tonic seizures revealed discharges that always spared the hamartoma but involved various cortical areas (Kahane et al., 1997). In the large RCH series (Harvey et al., 2003) and French series (Delalande and Fohlen, 2003), none of the patients underwent chronic recording with intracranial EEG to document HH seizure origin, and only a minority of those surgical cases in the literature have been studied as such. 3.4. PET and ictal SPECT Functional imaging studies in patients with HH and seizures are few. Positron emission tomography (PET) studies are scarce and report either scattered areas of cortical hypometabolism (Kitajima et al., 1998) or regional hypometabolism, the lateralization of which is concordant with asymmetric HH attachment (Palmini
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et al., 2002). SPECT studies have been performed more often (Acilona Echeverria et al., 1994; Kuzniecky et al., 1997, 2001; DiFazio and Davis, 2000; Khadilkar et al., 2001) and, in the RCH series, were pivotal in leading to surgery in our first operated patients (Harvey et al., 1998). Several authors have reported patients in whom injection of radioisotope during gelastic seizures demonstrated focal hyperperfusion in the region of the HH (Kuzniecky et al., 1997, 2001; Harvey et al., 1998; DiFazio and Davis, 2000). In the RCH series of 20 patients studied with subtraction ictal-interictal SPECT, 13 showed significant HH hyperperfusion, and ictal laughter was predictive of this (unpublished observations). In addition to HH hyperperfusion, asymmetric ictal (and less frequently interictal) rCBF patterns were seen, with abnormalities usually ipsilateral to the side of predominant HH attachment, perhaps suggesting preferential spread (Fig. 3).
Fig. 3. Coregistered axial (top row), sagittal (middle row), and coronal (bottom row) SPECT images of regional cerebral blood flow in a 13-year-old girl with a large hypothalamic hamartoma and refractory gelastic seizures. Ictal SPECT (left column), interictal SPECT (second column), subtraction interictal from ictal SPECT (third column), and subtraction SPECT overlaid on MRI (right column) are shown following coregistration of SPECT and MRI data sets and slicing in identical planes and positions. The ictal SPECT study was obtained following injection of Tc-99m-HMPAO 19 s after cessation of a typical gelastic seizure of 64-s duration. Ictal hyperperfusion is demonstrated in the hypothalamic hamartoma.
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4. Summary Historically, the findings of interictal and ictal EEG recordings in patients with HH, both with scalp and intracranial electrodes, led to the incorrect assumptions that seizures arose in the cerebral cortex, that the HH simply an epiphenomenon in a more widespread but occult cerebral dysplasia, and that in patients with SGE, there was either diffuse dysgenesis or irreversible brain damage. It was not until the results of depth electrode EEG recordings and ictal SPECT studies were reported, and the benefits of HH resection were realized, that the concept of HH seizure origin became accepted. While the mechanisms of spike-wave generation, tonic seizure evolution, and cognitive deterioration remain elusive in this syndrome, there is now acceptance of a pivotal role of the intrinsically epileptogenic HH, with potential for improved seizure control, behavior, and cognition with its resection or disconnection. As previously stated, the most important aspects of the preoperative evaluation are assessments of endocrine status, cognition and behavior, seizure and EEG evolution, and HH anatomical characteristics. Ictal EEG recordings, SPECT studies, and intracranial EEG are probably of limited value in the preoperative investigation of patients with HH, and may potentially lead the epileptologist to believe that seizures do not originate in the HH and that HH resection is not indicated. Ictal EEG recordings and SPECT studies might play a role in excluding a neocortical focus, but there is a great risk of seeing erroneous, pseudolocalization. A careful review of a high-quality MRI and attention to seizure manifestations is more likely to better exclude another source of seizures. Depth EEG recordings need only be considered if there is definite, additional pathology on MR imaging, and seizure localization is not apparent from the noninvasive evaluation. References Acilona Echeverria, V, Casado Chocan, JL, Lopez Dominguez, JM, Aguilera Navarro, JM, Marques, ME and Munoz, VC (1994) Gelastic seizures, precocious puberty and hypothalamic hamartomas. A case report and the contributions of Single Photon Emission Computed Tomography (SPECT). Neurologia, 9: 61–64. Arita, K, Ikawa, F, Kurisu, K, Sumida, M, Harada, K, Uozumi, T, Monden, S, Yoshida, J and Nishi, Y (1999) The relationship between magnetic resonance imaging
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